Parallel stirring apparatus

ABSTRACT

An apparatus and method useful for simultaneously stirring a plurality of reaction mixtures has been developed. The apparatus includes N gears, where N is at least 2, with each gear having a hub and multiple teeth, material removed from the hub to form a passage through the gear; a motor associated with at least one gear; N reaction vessels associated with the N gears; and a stirrer fastened to each of the gears, with the stirrers extending into the reaction vessels.

FIELD OF THE INVENTION

The present invention is an apparatus for stirring or mixing and aprocess for adding reagent to a plurality of reaction vessels whilesimultaneously stirring the plurality of reaction mixtures.

BACKGROUND OF THE INVENTION

When reagent is added to a reaction mixture, it is generally considerednecessary to stir the mixture in order to achieve a homogeneous mixtureand to prevent phase separation. Stirring is even more important whenthe reaction mixture is viscous. If a viscous reaction mixture was notstirred upon the addition of a reagent, it is likely that the reagentwould not be distributed homogeneously throughout the reaction mixturewhich could result in an incomplete reaction and misleading orinconclusive data.

Recently, chemical reactions and materials syntheses have been conductedusing combinatorial techniques. In the combinatorial approach, multiplereactions are conducted in parallel. Applying the combinatorial methodsto more viscous materials gave rise to a need for parallel stirring ormixing. It became especially desirable to have the capability to stir anarray of parallel reaction mixtures while reagent is being added. Othershave used agitation-type mixing in parallel; see WO 98/39099. However,the present invention provides the advantages of adding reagent whilestirring and adding the reagent to a central portion of thecross-section of the reaction vessel. Additionally, magnetic or shakingstirrers may not be effective enough to homogenize viscous gels. Thepresent invention is designed to simulate the high shear mixers used inlarge-scale material preparations.

SUMMARY OF THE INVENTION

The invention is an apparatus for mixing a reaction mixture in a vesselwhile at the same time adding reagent to the reaction mixture. Theinvention is particularly useful when the reaction mixture is viscous asis commonly found in sol gel reactions. The apparatus involves N rotarydrive members, where N is at least 2, where each rotary drive member hasa hub with material removed from the hub to form a passage through therotary drive member; a motor drivably associated with at least onerotary drive member; and a stirrer engaged with each of the rotary drivemembers. A preferred embodiment of the apparatus involves N gears, whereN is at least 1, with each gear having a hub and multiple teeth.Material is removed from the hub to form a passage through the hub ofthe gear. A motor is associated with at least one gear in order to drivethe rotation of the gear. N reaction vessels are associated with the Ngears; and a stirrer is fastened to each of the gears, with the stirrerextending into the reaction vessel.

The invention also encompasses a method for adding reagent to aplurality of reaction vessels where each reaction vessel contains areaction mixture. The method begins with providing the apparatusdescribed above. Then reagent is added to the plurality of reactionvessels via conduits that are in fluid communication with the passagethrough the gear. The multiple reaction mixtures are simultaneouslystirred during the addition of reagent by activating the motor anddriving the gears.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional side view of one embodiment of the generalapparatus.

FIG. 2 is a top view of a gear cassette.

FIG. 3 is a side view of the gear cassette of FIG. 2 and

FIG. 4 is an end view of the gear cassette of FIG. 2.

FIG. 5 is a sectional side view of the gear support and hollow shaftembodiments.

FIG. 6 is a sectional side view of one embodiment of the stirrer. Thedrawings have been simplified by deleting other equipment used inconjunction with the apparatus of the present invention.

DETAILED DESCRIPTION OF THE APPARATUS

In general terms the apparatus of the present invention includes atleast two rotary drive members. It is preferred that the rotary drivemembers are gears, each having a hub and multiple teeth, however, otherrotary drive members may be used such as wheels driven by friction orbelt and wheel assemblies. For ease of understanding and withoutlimiting the scope of the invention, the description below refers to thepreferred embodiment containing gears. The gears are preferablypositioned so that the teeth of one of the gears engage the teeth of theother gear. The hub of the gears has material removed so as to form apassage through the gear. A motor is used to rotate the gears. Attachedto each of the gears is at least one stirrer. Each stirrer extends intoa vessel which is one of an array of reaction vessels. The positioningand geometry of the stirrer is such that reagent may be added throughthe passage of the gear and into the reaction mixture. The apparatus isused for stirring or mixing a reaction mixture, particularly whilereagent is being added to the mixture, and the apparatus can be usedwith essentially any synthetic reaction. Reagent is added to theplurality of reaction vessels via a plurality of conduits that are eachin fluid communication with one passage through a gear. During additionof the reagent, the motor is activated and the gears are rotatingthereby driving the stirrer in a circular pattern so that all of thereaction mixtures are being simultaneously stirred during the reagentaddition.

FIG. 1 shows a general exploded cross sectional view of the apparatus. Acentral block 2, defines an array of wells 4, which are the reactionvessels. The gears 6 have a portion of the hub removed to form passages8, and have additional material removed to form peg inputs 12. Gears 6are supported by gear support framework 10. Gears 6 engage one anotherand are driven by motor 20 which is controlled by microprocessor 22.Both gear support 10 and central block 2 have guides, 28 and 26,respectively, for use with guide pins 24. Guide pins 24 operate to alignpassages 8 over wells 4. Stirrers 16 have material removed to form peginputs 18. Stirrers 16 engage the gears 6 via pegs 14 which are insertedinto gear peg inputs 12 and stirrer peg inputs 18.

As noted above, many types of rotary drive units may be employed in thepresent invention, and the use of gears having a hub and multiple teethis merely the preferred embodiment of the invention. For example, wheelsinterconnected by one or more belts may be employed or wheels thatengage one another based upon frictional interactions may be employed.However, the bulk of the discussion below will focus on the preferredembodiment that employs gears. In the preferred embodiment, at least twogears are used in combination in the present preferred apparatus. Whenthe array of reaction vessels contains greater than two vessels, it ispreferred that the number of gears equal the number of reaction vessels.For example, a combinatorial stirrer used with an array of 96 reactionvessels would preferably contain 96 gears. The gears may be constructedout of stainless steel, plastic, and plastic coated metal. The gears maybe coated to increase chemical resistance. The gears each contain acentral hub and a multiplicity of teeth or cogs along the edge of thehub.

A portion of the central hub is removed to form at least one passagethrough the hub. The position of the passage through the hub and thesize of the passage through the hub are dependent upon the particularapplication of the apparatus. As discussed in more detail below, theprimary purpose of the passage through the hub is to introduce fluidsuch as reagents to the reaction vessels while stirring the reactionmixture. The passage is located at the center of the hub. The size ofthe passage through the hub may be dependent upon the fluid deliverysystem being employed and the gear size. The shape of the passage may beany of a variety of shapes. For ease of manufacture, a cylindrical boremay be preferred. A funnel shaped passage may also be advantageous infacilitating the entry of a fluid stream and minimizing the probabilityof fluid leaving the reaction vessel. Yet another alternative allows fora septum to be placed within the passage to prevent evaporation ormaterial exiting the reaction vessel. The fluid delivery system wouldpenetrate the septum for fluid delivery to the reaction vessel. It ispreferred that a hollow shaft be positioned within the passage throughthe hub. The shaft would rotate with the rotation of the gears, andwould extend beyond the gear.

It is preferred that the gears be of a size appropriate to the size andarrangement of the vessels in the array of reaction vessels. It ispreferred that the gears are sized so that the teeth of a first gearthat is associated with a first vessel engage the teeth of a second gearthat is associated with a second vessel. Alternatively, auxiliary gearsmay be interspersed between the gears that are associated with thevessels.

Groups of vessels may be defined so that the gears associated within agroup of vessels engage one another. Multiple groups may be definedwithin the array of gears and associated reaction vessels, with themember gears of a first group being unable to engage the member gears ofa second group. For example, if the array of reaction vessels isarranged in a grid pattern, the gears may be grouped by rows or columnsso that the gears of a first row or column do not engage the gears of asecond row or column. The gears within a single row or column may engageeach other. Alternatively, the grid of gears may be grouped in quadrantsor sections with the gears within a quadrant or section capable ofengaging only other gears within the same quadrant or section. The gearsmay be positioned all in the same plane but dispersed in such a way thatonly the gears of a defined group engage one another. In anotherembodiment, the gears may be positioned at different heights so thatonly gears of a defined group engage one another.

In combinatorial techniques, it is preferred to manipulate equipment inunits as opposed to individually. For example, it is preferred that thearray of reaction vessels be commonly supported or interconnected sothat the array may be manipulated, moved, or handled as a single unit.The same preference applies to the present invention as well. It ispreferred that the array of gears be supported in a configuration thatwould allow the array to be manipulated, moved, and handled as a unit,such as, for example, as a cassette of gears. The cassette may containone or more support plates to position the gears and to provide a rigidstructure that may be handled as a unit. Bearings may be used inconjunction with the support plates and gears to allow the gears torotate within the framework of the support plates. It is preferred thatthe cassette have a guide, such as, for example, a guide pin, that is inalignment with another guide on the array of reaction vessels to aid inthe alignment of the cassette in reaction to the array of reactionvessels. It is further an option to incorporate a locking device toretain the gear support in the proper position in relation to the arrayof reaction vessels.

Each gear may be optionally further equipped with a means for attachingat least one stirrer. For example, the gears may have material removedfor the stirrer screw or snap into, or for a peg to fit into, or thegears may have a protrusion or flap for affixing to the stirrer. Thegears may be equipped with electromagnets for the attachment of thestirrers. Optionally, the stirrer may be attached to a hollow shaft thatmay be positioned within the passage through the hub, extending belowthe gear and the cassette.

One possible gear arrangement is shown in FIG. 2, FIG. 3, and FIG. 4.FIG. 2 is a top view of a gear cassette, while FIG. 3 is a side view ofthe same cassette and FIG. 4 is an end view of the same cassette. Gears6 are arranged in two rows with each gear in a row engaging one another.Note that in another embodiment, the gears of the two rows may alsoengage one another. Gears in the first row are driven by motor 20 a viaa drive shaft and gears in the second row are driven by motor 20 b via adrive shaft. Again note that in another embodiment, all gears may bedriven by a single motor. FIG. 3 and FIG. 4 show that the gears in thefirst row are positioned at a first height, and the gears in the secondrow are positioned at a second height. While the figures show onepossible gear arrangement, it may be preferred, especially where thereaction vessels are evenly distributed with a constant center-to-centerdistance, that all the gears engage one another, and be driven by asingle motor.

FIG. 5 shows the gear support framework and the hollow shaft embodiment.The hollow shafts 36 are positioned within the passages through the hubof the gears 6. The rotary motion of the gears also turns hollow shafts36. Bearings 30 allow for the rotation of the hollow shaft while beingsupported by bearing support plates 32 and cover plate 34. Hollow shafts36 have material removed for the insertion of pegs 14 to which a stirrerwould be attached (not shown).

At least one motor is used to drive the rotation of the gears. A singlemotor may be used to drive all the gears, or several motors may beemployed. When the gears are in defined groups, a single motor may beused for each of the groups. It is preferred that the motor be capableof operating at different speeds so that speed may be set or adjusted toconform to the viscosity of the reaction mixture or reagents beingmixed. The speed may also be adjusted dynamically, such as beginningslowly and increasing with time to a set maximum and then decreasingwith time. The speed could be held constant at any point for theaddition of reagents. The control of the speed may be adjusted at themotor itself, or the motor could be connected to a microprocessorcontroller through which the speed could be controlled.

In yet another embodiment, the motor may be connected to a timer andprogrammed to activate at specific times. For example, the timer mayactivate the motor just prior to the time of the reagent addition andstop the motor at or for a set time period after reagent addition.Alternatively, the motor may be interconnected with the reagent deliverysystem so that activation of the reagent delivery system also activatesthe motor. All of the above may be controlled through a centralmicroprocessor.

The one or more stirrers that are attached to the gear or to a hollowshaft positioned with the passage through the hub of the gear may be ofany of a variety of styles or shapes constructed from a variety ofmaterials. The specific shape selected, as well as the material used,may be dependent upon the particular application. A suitable stirrerwill be able to provide sufficient mixing in the reaction mixture so asto form a homogeneous mixture. A suitable stirrer would also allow forthe addition of reagents, preferably at a location in the vicinity ofthe center portion of the cross-section of the reaction vessel. Theshape and design of the stirrer should not operate to pull material outof the reaction vessels.

The stirrers may be constructed of material such as Teflon™, glass,quartz, stainless steel, ceramic, polypropylene, and polyethylene. Thematerial chosen is preferably chemically resistant to the reactants andproducts in the reaction mixture. The stirrer may also have a coating ofa second material. The stirrers may be permanently attached to the gearsor to the hollow shafts positioned within the passage through the hub ofthe gears, however, it is more preferred that the stirrers may bedetached and removed from the gears or hollow shafts. For example,magnetic or loose couplings would allow the stirrers to be released andremain in the reaction vessels. Detachment would allow the stirrers toremain in the reaction vessels and perhaps conserve reaction productmaterial. Wash techniques may be performed prior to the stirrer beingremoved from the vessel. It is envisioned that the stirrer may alsofunction as an agitator to break up solid products or by-products. It isfurther envisioned that the stirrer may be integrated into the reactionvessel, to which the gear assembly couples when it is placed inalignment.

One suitable design for the stirrer is shown in FIG. 6, which is asectional view. Turning to FIG. 6, central block 2 having well 4 definesthe reaction vessel. Stirrer 16 is positioned within the reaction vesseland is attached via pegs 14 to gear 6. As gear 6 rotates, stirrer 16also rotates, mixing the reaction mixture contained in well 4. The crosssectional shape of stirrer 16 is in the general shape of the uppercaseletter “U”. Stirrer 16 has a total of four vanes 16 a, with each pair ofvanes supported by a crossbar 16 b. The crossbars 16 b intersect at acenter portion of the reaction vessel. The shape of the stirrer allowsfor the introduction of reagents through passage 8 of gear 6 and intothe reaction mixture while the mixture is actively being stirred. In analternative embodiment, the cross sectional shape of stirrer 16 is inthe general shape of the uppercase letter “H”, accomplished by attachingthe crossbars 16 b to vanes 16 a at a midsection of vanes 16 a. Thisdescription is directed at a preferred design, but other stirrer designswould be suitable. Also, multiple stirrers may be used within a singlereaction vessel, each being attached to the gear associated with thevessel.

The array of reaction vessels may be any of those known in the art,especially those used for combinatorial synthesis of materials. Apreferred array of reaction vessels is described in WO 98/36826. Thearray contains at least two individual reaction vessels, and may containtens or hundreds of individual reaction vessels. It may be preferredthat the reaction vessels have a rounded bottom to avoid precipitatecollecting in corners. For ease of understanding, the reaction vesselsare shown herein as cylindrical bores in a central block. However, thisexample is merely for simplicity and is not intended to limit the scopeof suitable reaction vessels. To maintain the alignment of the arrays ofreaction vessels and the corresponding array of gears, guide pins,recesses, frames or other such alignment devices may be used.

As discussed above, it is preferred to add reagents to a central portionof the cross section of the reaction vessel to aid in achievinghomogeneity of the mixture, especially when dealing with more viscousreaction mixtures such as those found in sol gel syntheses. It is mostpreferred to add reagents slightly off-center of the cross section ofthe reaction vessel. Therefore, the passage through the hub of the gearor through the hollow shaft is in alignment with an opening of thereaction vessel. A reagent delivery system is arranged so that reagentmay be added to the reaction vessel through the passage in the hub ofthe gear, or through the hollow center portion of the hollow shaft. Thereagent delivery system may be any of currently known delivery systems,and the design of the reagent delivery system is not critical to thesuccess of the invention. Successful delivery systems will be thosecapable of adapting the introduction of the reagents to the passagethrough the hub of the gear or through the hollow shaft.

It is envisioned that the present invention has applications beyondcombinatorial techniques and may be employed in more traditional singlereaction experimental designs. This embodiment is as described aboveexcept that there is only one reaction vessel, associated with a singlemotor-driven gear. The key advantages of the present invention such asthe capability of adding reagent while actively stirring and adding thereagent to a central portion of the cross section of the reaction vesselare also beneficial in a single reaction vessel setting.

What is claimed is:
 1. An apparatus for parallel stirring comprising: a)N rotary drive members, where N is at least 2, each rotary drive memberhaving a hub defining a passage through the rotary drive member; b) asupport associated with the rotary drive members; c) a motor drivablyassociated with at least one rotary drive member; d) N reaction vesselsassociated with the N rotary drive members; e) a stirrer engaged witheach of said rotary drive members wherein the stirrers extend into thereaction vessels; and f) a locking device engaging the reaction vesselsand the support.
 2. The apparatus of claim 1 further comprising at leastone guide pin associated with the support and the reaction vessels. 3.An apparatus for parallel stirring comprising: a) N gears, where N is atleast 2, each gear having a hub and multiple teeth with the hub defininga passage through the gear; b) a support associated with the gears; c) amotor drivably associated with at least one gear; d) N reaction vesselsassociated with the N gears; e) a stirrer engaged with each of saidgears, the stirrers extending into the reaction vessels; and a lockingdevice engaging the reaction vessels and the support.